This invention relates to compositions and methods for treating cancers.
In many animal tumor models, T cells play an important role in tumor rejection. A variety of tumor antigens recognized by CD4+ or CD8+ tumor reactive T cells have been identified on both murine and human tumors (1). CD8+ cytotoxic lymphocytes (CTL) are of particular interest because these cells specifically recognize tumor cells and kill them. Therefore, an important goal in cancer immunotherapy is to activate tumor-specific CTL.
Study of antigens recognized by CD8+ T cells on human melanoma has identified several MHC-restricted tumor epitopes that correspond to nonmutated or mutated peptides derived from various self proteins (2). Several of these peptides are derived from nonmutated differentiation proteins such as tyrosinase, Melan-A/Mart-1, and gp100. These proteins are specifically expressed in most melanocytes/melanomas, and thus, the HLA-restricted epitopes are presented by most melanoma cells from patients expressing the relevant HLA molecules. Therefore, these antigens could be the targets of immunotherapeutic strategies that are based on immunization against tumor epitopes.
Other antigens expressed on tumor cells have also been described, for example, a peptide derived from an intron sequence of the gene that codes for N-acetylglucosaminyl-transferase V (GnT-V) (3). This intron is specifically expressed in melanoma cells and is present in about 50% of melanoma cells.
Various vaccination protocols designed to induce specific anti-tumor CTL responses against these epitopes have been developed, including protocols that use free peptide in IFA (4), recombinant viral vectors (5-7), or dendritic cells (8-11). The application of these approaches to human vaccination remains limited due to potential toxicity of adjuvants, bias towards the response against vector-derived epitopic peptide, or because they are “labor-demanding” (in vitro manipulated DC).
Previously, recombinant plasmids have been used for the expression of Bordetella sp. adenylate cyclase (cyaA) and a heterologous DNA inserted in a permissive site of CyaA. These plasmids and resulting recombinant proteins have been useful for inducing immune responses. The immune responses elicited have been in CD8+ T lymphocytes with class I major histocompatibility complexes, as well as in CD4+ T lymphocytes with class II major histocompatibility complexes. (See U.S. Pat. Nos. 5,503,829, 5,679,784, and 5,935,580.) More specifically, the recombinant proteins can be delivered to CD11b expressing cells, such as dendritic cells. (See European Patent Application EP1 188 446 A1, “Proteinaceous vectors for molecule delivery to CD11b expressing cells”, and WO/2122169 A2 “Vectors for Molecule Delivery to CD11b Expressing Cells”, corresponding to U.S. Pat. No. 387,486, and European Patent Application No. 03291486.3, “Modified Bordetella Adenylate Cyclase Comprising or Lacking CD11b/CD18 Interaction Domain and Uses thereof”.) See also, El-Azami-El-Idrissi, et al., 2003, Interaction of Bordetella pertussis Adenylate Cyclase with CD11b/CD18, J. Biol. Chem., vol. 278, pp. 38514-21.
There exists a need in the art for new antitumor treatments that allow for specific targeting to immune cells and T cell responses. These new strategies should result in specific amplification of immune responses against tumoral antigens.